1,721,598 research outputs found
Molecular pathogenesis of heart failure: CaMKII inhibition as a novel therapeutic approach
No full textRole of CaMKII for signaling and regulation in the heart
No full textThe Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is the CaMK isoform predominantly found in the heart. Cardiac myocytes signaling during excitation-contraction coupling (ECC) is described by the increase in intracellular Ca(2+) concentration. In consequence, CaMKII is activated thereby phosphorylating several important Ca(2+) handling proteins with multiple functional consequences for cardiac myocytes. Specific CaMKII overexpression in the heart and in isolated myocytes of animals can exert distinct and novel effects on ECC. CaMKII activity and expression are reported to be increased in cardiac hypertrophy, in human heart failure, as well as in animal models thereby contributing to cardiac disease through a regulation process termed excitation-transcription coupling (ETC). In the present review important aspects of the role of CaMKII in ECC and ETC are summarized with an emphasis on recent novel findings
A Novel Mechanism for the Treatment of Angina, Arrhythmias, and Diastolic Dysfunction: Inhibition of Late INa Using Ranolazine
No full textInhibition of the persistent or late Na current (I-Na) using ranolazine (Ranexa) represents a novel mechanism of action that was approved in the United States in 2006 and only recently in the European Union for use in patients with stable angina pectoris. In general, myocardial ischemia is associated with reduced adenosine triphosphate fluxes and decreased energy supply, resulting in severe disturbances of intracellular ion homeostasis in cardiac myocytes. In the recent years, increased late I-Na was suggested to contribute to this phenomenon by elevating intracellular Na concentration with subsequent rise in diastolic Ca levels by means of the sarcolemmal Na-Ca exchange system. Ranolazine, a specific inhibitor of late I-Na, reduces Na influx and hence ameliorates disturbed Na and Ca homeostasis. This is associated with a symptomatic improvement of angina in patients unlike other antianginal drugs without affecting heart rate or systemic blood pressure as shown in placebo-controlled studies. Therefore, ranolazine is a useful new option for patients with chronic stable angina not only as an add-on therapy. New clinical and experimental studies even point to potential anti arrhythmic effects, beneficial effects in diastolic heart failure, and under hyperglycemic conditions. In the present article, the relevant pathophysiological concepts for the role of late I-Na inhibition are reviewed and the most recent data from basic studies and clinical trials are summarized
CaMKIIdelta overexpression in hypertrophy and heart failure: cellular consequences for excitation-contraction coupling
No full textCa/calmodulin-dependent protein kinase II delta (CaMKII delta) is the predominant isoform in the heart. During excitation-contraction coupling (ECC) CaMKII phosphorylates several Ca-handling proteins including ryanodine receptors (RyR), phospholamban, and L-type Ca channels. CaMKII expression and activity have been shown to correlate positively with impaired ejection fraction in the myocardium of patients with heart failure and CaMKII has been proposed to be a possible compensatory mechanism to keep hearts from complete failure. However, in addition to these acute effects on ECC, CaMKII was shown to be involved in hypertrophic signaling, termed excitation-transcription coupling (ETC). Thus, animal models have shown that overexpression of nuclear isoform CaMKII delta(B) can induce myocyte hypertrophy. Recent study from our laboratory has suggested that transgenic overexpression of the cytosolic isoform CaMKII delta(C) in mice causes severe heart failure with altered intracellular Ca handling and protein expression leading to reduced sarcoplasmic reticulum (SR) Ca content. Interestingly, the frequency of diastolic spontaneous SR Ca release events (or opening of RyR) was greatly enhanced, demonstrating increased diastolic SR Ca leak. This was attributed to increased CaMKII-dependent RyR phosphorylation, resulting in increased and prolonged openings of RyR since Ca spark frequency could be reduced back to normal levels by CaMKII inhibition. This review focuses on acute and chronic effects of CaMKII in ECC and ETC. In summary, CaMKII overexpression can lead to heart failure and CaMKII-dependent RyR hyperphosphorylation seems to be a novel and important mechanism in ECC due to SR Ca leak which may be important in the pathogenesis of heart failure
Experimental Antiarrhythmic Targets: CaMKII Inhibition - Ready for Clinical Evaluation?
No full textIn the recent years, Ca2+/calmodulin-dependent protein kinase II (CaMKII) was suggested to be associated with cardiac hypertrophy and heart failure but also with arrhythmias both in animal models as well as in the human heart. This article focuses on the role of CaMKII for excitation-contraction coupling but more explicitly it highlights major CaMKII-dependent proarrhythmogenic mechanisms including SR Ca2+ leak and late Na+ current. Because a clinical significance of CaMKII is implied for both mechanisms, CaMKII inhibition is suggested to be a therapeutical approach in the near future
Pathophysiology of chronic myocardial ischemia
No full textMyocardial ischemia is caused by a mismatch between myocardial oxygen supply and myocardial oxygen requirements. Obstructive coronary artery disease (CAD) is the most common cause for myocardial ischemia. Although coronary bypass graft (CABG) surgery und percutaneous coronary interventions (PCI) are established therapies to treat CAD, 10 years after CABG or PCI 40% of the patients still have angina pectoris. Besides obstructive CAD, chronic myocardial ischemia can be induced by small vessel disease and endothelial dysfunction that is not treatable with CABG or PCI. On the cellular basis myocardial ischemia leads to a sodium overload that is caused by an increase in the late sodium current (I (Na, late)). The increased intracellular sodium concentration leads to a mode switch of the sodium/calcium exchanger (NCX) that now eliminates sodium from the cell and transports calcium into the cell. The resulting calcium overload activates the contractile myofilaments causing an increased wall tension in diastole which compromises the microcirculation and intensifies myocardial ischemia
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